Process for the preparation of substituted pyrimidines

ABSTRACT

The invention relates to a process for the preparation of substituted pyrimidines of formula I,  
                 
 
     wherein  
     R 1 , R 2 , R 3 , R 4  and X are as defined in claim  1,    
     which comprises reacting an amidine of formula II,  
                 
 
     or a salt thereof, with a  3,3 —disubstituted vinylcarbonyl compound of formula III  
                 
 
     wherein L represent a halogen atom or a group of formula —X—R 2 ,  
     (a) in an inert solvent, in the presence of a base and a compound of formula IV  
     H—X—R 2   (IV) 
     in the event that L represent a halogen atom, or  
     (b) in an inert solvent and in the presence of a base, in the event that L represents a group of formula —X—R 2 .

BACKGROUND OF THE INVENTION

[0001] The present invention relates to an improved process for thepreparation of substituted pyrimidines.

[0002] Pyrimidines, which are substituted in the 4-position by ahydrocarbyloxy or hydrocarbylthio group are of great commercial interestas highly effective pesticides or pharmaceuticals. U.S. Pat. No.3,498,984 discloses 2-phenyl-4-thiopyrimidines with interestingpharmaceutical properties. U.S. Pat. No. 5,824,624 describes herbicidalcompositions comprising 2-phenyl-4-oxypyrimidines. The InternationalPatent Applications WO 98/40379 and WO 98/56789 disclose herbicidal4-oxypyrimidines, in which a 5-membered heteroaromatic group is attachedto the 2-position position of the pyrimidine moiety.

[0003] These compounds can be prepared for example in a multi-stepprocess including the steps of treating a benzamidine hydrochloride witha substituted acetylacetate in the presence of a strong base to form a2-phenylpyrimid-4-one, which is subsequently treated with a halogenatingagent, in particular a phosphoryl halide to yield a4-halo-2-phenylpyrimidine, which is reacted with an alcohol or athioalcohol.

[0004] However, this process cannot be used for manufacture ofrelatively large quantities on an industrial scale due to the high riskof uncontrollable heat generation during the aqueous work up of thehalogenation step.

[0005] W. Schroth et al., disclose the preparation of1,3-thiazin-6-thiones by condensation of 3,3-dichloroacrolein andthioamides in the presence of trifluoroborane.

[0006] However, there is no motivation to apply this reaction on themanufacture of substituted pyrimidines, especially, sincetrifluoroborane is not applicable in large scale productions.

SUMMARY OF THE INVENTION

[0007] The present invention provides an effective and efficient processfor the preparation of substituted pyrimidines of formula I,

[0008] wherein

[0009] R¹ and R² ea ch independently represent an optionally substitutedalkyl, cycloalkyl, phenyl or heteroaryl group,

[0010] R³ and R⁴ each independently represent a hydrogen atom or anoptionally substituted alkyl or phenyl group, and

[0011] X represents O or S.

[0012] which comprises

[0013] reacting an amidine of formula II,

[0014] or a salt thereof, wherein R¹ has the meaning given for formulaI, with a 3,3-disubstituted vinylcarbonyl compound of formula III

[0015] wherein R³ and R⁴ have the meaning given, and

[0016] L represent a halogen atom or a group of formula —X—R²,

[0017] (a) in an inert solvent, in the presence of a base and a compoundof formula IV

H—X—R²  (IV)

[0018]  wherein X and R² have the meaning given, in the event that Lrepresent a halogen atom, or

[0019] (b) in an inert solvent and in the presence of a base, in theevent that L represents a group of formula —X—R².

[0020] It is, therefore, an object of the present invention to providean efficient new process for the preparation of substituted pyrimidines.

[0021] Other objects and advantages of the present invention will beapparent to those skilled in the art from the following description andthe appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] When any groups are designated as being optionally substituted,the substituent groups which are optionally present may be any of thosecustomarily employed in the modification and/or development ofpesticidal/pharmaceutical compounds and are especially substituents thatmaintain or enhance the herbicidal activity associated with thecompounds of the present invention, or influence persistence of action,soil or plant penetration, or any other desirable property of suchherbicidal compounds. There may be one or more of the same or differentsubstituents present in each part of the molecules.

[0023] In relation to moieties defined above as comprising an optionallysubstituted alkyl or cycloalkyl group, specific examples of suchsubstituents include phenyl, halogen atoms, nitro, cyano, hydroxyl,C₁₋₄-alkoxy, C₁₋₄-haloalkoxy and C₁₋₄-alkoxycarbonyl groups.

[0024] In relation to moieties defined above as comprising an optionallysubstituted phenyl group or heteroaryl group, optional substituentsinclude halogen, especially fluorine, chlorine and bromine atoms, andnitro, cyano, amino, hydroxyl, C₁₋₄-alkyl, C₁₋₄-alkoxy, C₁₋₄-haloalkyl,C₁₋₄-haloalkoxy, C₁₋₄-haloalkylthio and halosulfanyl groups such as SF₅.1 to 5 substituents may suitably be employed, 1 to 2 substituents beingpreferred. Typically haloalkyl, haloalkoxy and haloalkylthio groups aretrifluoromethyl, trifluoromethoxy, difluoromethoxy andtrifluoromethylthio groups.

[0025] In general terms, unless otherwise stated herein, the term alkylas used herein with respect to a radical or moiety refer to a straightor branched chain radical or moiety. As a rule, such radicals have up to10, in particular up to 6 carbon atoms. Suitably an alkyl moiety hasfrom 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms. Apreferred alkyl moiety is the methyl or especially the ethyl group.

[0026] In general terms, unless otherwise stated herein, the termcycloalkyl as used herein with respect to a radical or moiety refers toa cycloalkyl radical which has up to 10, in particular up to 8 carbonatoms. Suitably a cycloalkyl moiety has from 3 to 6 carbon atoms,preferably from 3 or 6 carbon atoms. A preferred cycloalkyl moiety isthe cyclopropyl, cyclopentyl and the cyclohexyl group.

[0027] In general terms, unless otherwise stated herein,the termheteroaryl as used herein with respect to a radical or moiety refers toa nitrogen containing 5- or 6-membered heteroaromatic radical or moiety.As a rule, such radicals exhibit at least one nitrogen atom and in thecase of the five-membered radicals optionally one oxygen or sulfur atom;they are preferably selected from the 5-membered azoles, diazoles,triazoles, thiazoles, isothiazoles, thiadiazoles, in particular pyrroleand pyrazole and the 6-membered azines and diazines, in particularpyridine, pyrimidine, pyridazine and pyrazine.

[0028] In a preferred embodiment R¹ represents an optionally substitutedphenyl, pyrid-3-yl, pyridazine-2-yl, pyrazine-3-yl, thiazol2-yl,oxazol-2-yl, 1,3,4-thiadiazol-2-y, 1,2,4-oxadiazol-2-yl,1,3,4-oxadiazol-2-yl, pyrazol-1-yl or C₃₋₆ cycloalkyl group.

[0029] In a preferred embodiment R₂ represents an optionally substitutedphenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4yl, pyrazol-5-yl, pyridazine-2-ylor C₃₋₆ cycloalkyl group.

[0030] The groups R¹ and R² each independently are preferablesubstituted by one or more alkyl, fluoroalky, alkoxy or fluoroalkoxygroup.

[0031] Suitable bases are weak organic or inorganic bases, preferablyalkali hydrogencarbonates, such as sodium hydrogencarbonate, alkalicarbonates, such as potassium carbonate or sodium carbonate, andtertiary amines, such as pyridine or triethylamine.

[0032] Further preferred embodiments of the process according to thepresent invention are a processes wherein:

[0033] the reaction is carried out in the presence of a base selectedfrom the group consisting of, alkali carbonates and tertiary amines, inparticular potassium carbonate or sodium carbonate;

[0034] the amidine of formula II to 3,3-disubstituted vinylcarbonylcompound of formula III molar ratio is from 1:5 to 1:0.5, in particularfrom 1:1.5 to 1:0.7, most preferred from 1:1.1 to 1:0.9;

[0035] the reaction step further comprises stirring a mixture consistingessentially of the amidine of formula II, the 3,3-disubstitutedvinylcarbonyl compound of formula III, an inert diluent, a base and anoptionally substituted alcohol, thioalcohol, phenol or thiophenol at atemperature from 0° C. to 150° C., preferably from 60° C. to 145° C., inparticular from 80° C. to 140° C., most preferred at about the boilingpoint of the diluent;

[0036] the inert diluent is selected from the group consisting ofacetonitril, benzene, toluene, xylene, hexane, cyclohexane,dichloromethane, tetrachloromethane, diethylether, diisopropylether,tert-butylmethylether, 2,2-dimethoxypropane, dimethoxyethane,diethoxyethane, tetrahydrofuran, tetrahydropyran, dimethylformamide,dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and dioxane,and a mixture thereof, in particular toluene, dimethoxyethane oracetonitril;

[0037] R¹ represents a phenyl group which is substituted by at least onehalogen atom, or at least one alkyl, alkoxy, haloalkyl or haloalkoxygroup, in particular a phenyl group which is substituted by one or twochlorine or fluorine atoms, or one or two C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄fluoroalkyl or C₁₋₄ fluoroalkoxy groups, R¹ is most preferably a4-trifluoromethylphenyl, difluoromethoxypyrid-2-yl or1-methyl-3-triflouromethylpyrazol 1-methyl-3-trifluoromethylpyrazol-5-ylgroup;

[0038] R¹ and R² each independently represent a phenyl group which issubstituted by at least one halogen atom, and/or at least one alkyl,alkoxy, haloalkyl or haloalkoxy group, X represents O, and whichcomprises that the reaction step is carried out in the presence of aphenol, which is substituted by at least one halogen atom, and/or atleast one alkyl, alkoxy, haloalkyl or haloalkoxy group, in particular aphenol which is substituted by one or two chlorine or fluorine atoms, orone or two C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ fluoroalkyl or C₁₋₄fluoroalkoxy groups, most preferred a 3-trifluoromethylphenol;

[0039] wherein the 3,3-disubstituted vinylcarbonyl compound of formulaIII is 3,3-dichloroacrolein.

[0040] The compounds of formula II or the salts thereof are preferablyoptionally substituted benzamidines or benzamidinum salts, mostpreferred 4-trifluoromethylbenzamidine, which can be prepared fromcommercially available optionally substituted benzonitriles, inparticular 4-trifluoromethylbenzonitril, by addition of ammonia orammonium salts.

[0041] Preferred benzamidinium salts are chlorides, sulfates, nitratesand carboxylates, in particular acetates and thioglycolates.

[0042] The 3,3-disubstituted vinylcarbonyl of formula III, wherein Lrepresents a halogen atom are commercially available or can be preparedby reaction of tetrahalometharies with vinylethers.

[0043] In a preferred embodiment of this invention, the1,1,1,3-tetrahalo-3-alkoxypropane obtained in this reaction can behydrolysed in-situ to obtain the corresponding vinylcarbonyl compound offormula III, which is subsequently reacted, preferably without furtherisolation and/or purification steps, i.e., in a one-pot-synthesis, withthe compound of formual II.

[0044] The 3,3-disubstituted vinylcarbonyl of formula III, wherein Lrepresents a group of formula —X—R^(2,) can be prepared by reaction of acompound of formula III, wherein L represents a halogen atom with acompound of formula IV

H—X—R²  (IV)

[0045] optionally in the presence of a base.

[0046] As a rule the reaction between the amidine of formula II, the3,3-disubstituted vinyl carbonyl compound of formula III and optionallythe alcohol, phenol, thioalcohol or thiophenol is carried out atelevated temperatures, preferably between 35° C. and 150° C., inparticular between 80° C. and 145° C., most preferred at boiling pointof the diluent.

[0047] The crude product obtained can be purified according to standardmethods for example by distillation in vacuo, chromatographic methods orcrystallization.

[0048] The reaction is as a rule completed within 5 to 50 hours, inparticular 10 to 25 hours.

[0049] In a particularly preferred embodiment of the process accordingto this invention 3,3-dichloroacrolein (1 mole) optionally diluted withan inert diluent, in particular acetonitril, is added to a mixtureconsisting of a benzamidine of formula II, wherein R¹ is a an optionallysubstituted phenyl group, in particular 4-trifluoromethylbenzamidine (1mole), an optionally substituted phenol, in particular3-trifluoromethylphenol (1.1 moles), potassium carbonate (3 to 5 moles)and a diluent, which is stirred under reflux. The reaction mixture isstirred for 10 to 40 hours under reflux. The reaction mixture is stirredfor 10 to 40 hours under reflux and subsequently cooled down to ambienttemperature, and filtered. The organic phase is concentrated in vacuo.The residue is washed with an organic solvent and the solvent isdistilled off. The residue is purified by chromatography.

[0050] The compounds of formula 1 obtainable according to the processaccording this invention are partly known and partly novel. Theinvention relates also to the novel compounds of formula 1A,

[0051] wherein R³ and R⁴ have the meaning given for formula 1, and R¹represents an optionally substituted C₃₋₈ cycloalkyl or pyrazin-2-ylgroup. R⁵ represents a halogen atom or a haloalkyl or haloalkoxy group,and W—V represents N—CH, S—CH, N—CH—CH, CH—CH—CH or N—N(R⁶), in which R⁶represents a C₁₋₄ alkyl group.

[0052] In order to facilitate a further understanding of the invention,the following illustrative examples are presented. The invention is notlimited to the specific embodiments described or illustrated, butencompasses the full scope of the appended claims.

EXAMPLE 1 Preparation of4-(3-Triflouromethylphenoxy)-2-(4-Triflouromethylphenyl)-Pyrimidine

[0053] 3,3-Dichloroacrolein (10 mmoles) diluted with acetonitril (50ml), is slowly added to a mixture consisting of a4-trifluoromethylbenzamidine (10 mmoles), 3-trifluoromethylphenol (11mmoles), potassium carbonate (40 mmoles) and acetonitril (100 ml), whichis stirred under reflux. When the addition of 3,3-dichloroacrolein iscompleted additional 4-trifluoromethylbenzamidine (0.5 mmoles) is added.The reaction mixture is stirred for 20 hours under reflux andsubsequently cooled down to ambient temperature and filtered throughsilica. The organic phase is washed with ethyl acetate and concentratedin vacuo. The residue purified by chromatography on Al₂O₃ (petrolethers/ethyl acetate: 2/1) to yield 3.25 g (85%) of the pure producthaving a melting point of 66-67° C.

[0054] Analogously are prepared3-methyl-4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine,5-4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine,4-phenoxy-2-(4-trifluoromethylphenyl)pyrimidine

EXAMPLES 2 TO 8 Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Trifluoromethylphenyl)-Pyrimidine,

[0055] Analogously to example 1 4-trifluoromethylbenzamidine or thesalts thereof are reacted with 3,3-dichloroacrolein in the presence of3-trifluoromethylphenol in different solvents at different temperatures

[0056] The reactants and solvents, the reaction temperature and yieldsare shown in table 1 in which the following abbreviations have beenused: TFBA 4-trifluoromethylbenzamidine TFBA * HCl4-trifluoromethylbenzamidine hydrochloride TFBA * Ac4-trifluoromethylbenzamidinium acetate TFBA * TG4-trifluoromethylbenzamidinium thioglycolate TBME tert-butylmethyletherDME dimethoxyethane

[0057] TABLE I Examples 2 to 8 Example starting material solventtemperature Yield (%) 2 TFBA acetonitril reflux 85 3 TFBA DME reflux 854 TFBA toluene 90° C. 72 5 TFBA TBME reflux 39 6 TFBA * HCl DME reftux84 7 TFBA * Ac DME reflux 81 8 TFBA * TG DME reflux 47

EXAMPLE 9 Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Trifluoromethylphenyl)-Pyrimidine

[0058] A mixture of 3,3-bis-(3-trifluoromethylphenoxy)-acrolein (10mmoles), 4-trifluoromethylbenzamidine (10 mmoles), potassium carbonate(10 mmoles) and acetonitril (100 ml), is stirred at 80° C. for fourhours. The reaction mixture is cooled down to ambient temperature andfiltered through silica. The organic phase is washed with ethyl acetateand concentrated in vacuo. The residue is purified by chromatography onAl₂O₃ (petrol ethers/ethyl acetate: 2/1) to yield 3.06 g (80%) of thepure product having a melting point of 66° C.

EXAMPLE 10 Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Trifluoromethylphenyl)-Pyrimidine

[0059] 3-Trifluoromethylphenol (5 mmoles) and subsequently3,3-dichloroacrolein (5 mmoles) are added to a mixture consisting of a4-trifluoromethylbenzamidinium acetate (5 mmoles), sodium carbonate (40mmoles) and acetonitril (35 ml), which is stirred under reilux. Thereaction mixture is stirred for 20 hours under reflux and subsequentlycooled down to ambient temperature and filtered through silica. Theorganic phase is washed with ethyl acetate and concentrated in vacuo.The residue is purified by chromatography on Al₂O₃ (petrol ethers/ethylacetate: 2/1) to yield 1.1 g (60%) of the pure product having a meltingpoint of 66-67° C.

EXAMPLE 11 Enhanced Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Trifluoromethylphenyl)-Pyrimidine

[0060] Water (20 mmoles) is added to a solution of1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25ml). The reaction mixture is stirred for 2 h under reflux. The resultingmixture is slowly added to a mixture consisting of a4-trifluoromethylbenzamidine hydrochloride (10 mmoles),3-trifluoromethylphenol (11 mmoles), potassium carbonate (60 mmoles) anddimethoxyethane (50 ml), which is stirred under reflux. When theaddition of 3,3-dichloroacrolein solution is completed additional4-trifluoromethylbenzamidine hydrochloride (1 mmoles) is added. Thereaction mixture is stirred for 2 hours under reflux and subsequentlycooled down to ambient temperature, filtered through silica, and theorganic phase is concentrated in vacuo. The residue is purified bychromatography on SiO₂ (petrol ethers/diisopropylether: 6/1) to yield3,07 g (80%) of the product having a melting point of 66-67° C.

EXAMPLE 12 Preparation of2-(4-Chlorophenyl)-4-(3-Trifluoromethylphenoxy) Pyrimidine

[0061] 3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35ml), is slowly added to a mixture consisting of a 4-chlorobenzamidinehydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles),potassium carbonate (40 mmoles) and dimethoxyethane (40 ml), which isstirred under reflux. When the addition of 3,3-dichloroacrolein iscompleted additional 4-chlorobenzamidine hydrochloride (1 mmoles) isadded. The reaction mixture is stirred for 3 hours under reflux andsubsequently cooled down to ambient temperature over night and filteredthrough silica. The organic phase is concentrated in vacuo. The residuewas purified by chromatography on Al₂O₃ (petrol ethers/ethyl acetate:20/1) to yield 2.79 g (80%) of the pure product having a melting pointof 92° C.

EXAMPLE 13 Preparation of4-(3-Trifluoromethylphenoxy)-2-(4-Fluorophenyl) Pyrimidine

[0062] 3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35ml), is slowly added to a mixture consisting of a 4-fluorobenzamidineacetate (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassiumcarbonate (40 mmoles) nd dimethoxyethane (40 ml), which is stirred underreflux. When the addition of 3,3-dichloroacrolein is completedadditional 4-fluorobenzamidine acetate (1 mmoles) is added. The reactionmixture is stirred for 3 hours under reflux and subsequently cooled downto ambient temperature over night and filtered through silica. Theorganic phase is concentrated in vacuo. The residue was purified bychromatography on Al₂O₃ (petrol ethers/ethyl acetate: 20/1) to yield2.52 g (75%) of the pure product having a melting point of 52° C.

EXAMPLE 14 Preparation of 2-Cyclopropyl-4-(3-Trifluoromethylphenoxy)Pyrimidine

[0063] 3,3-Dichloroacrolein (10 mmoles) diluted with dimethoxyethane (35ml), is slowly added to a mixture consisting of a cyclopropylcarbamidinehydrochloride (10 mmoles), 3-trifluoromethylphenol (11 mmoles),potassium carbonate (40 rnmoles) and dimethyoxyethane (40 ml), which isstirred under reflux. When the addition of 3,3-dichloroacrolein iscompleted additional cyclopropylcarbamidine hydrochloride (1 mmoles) isadded. The reaction mixture is stirred for 3 hours under reflux andsubsequently cooled down to ambient temperature over night and filteredthrough silica. The organic phase is concentrated in vacuo. The residuewas purified by chromatography on Al₂O₃ (petrol ethers/ethyl acetate:20/1) to yield 2.1 g (75%) of the pure product having as a colorlessliquid; ¹H NMR (CDC1₃); δ=2.10 ppm (m, N=C(=N)−CH).

EXAMPLE 15 Preparation of2-(4-Flourophenyl)-4-(5-Trifluoromethyl2-Methylpyrazol-3-Yloxy)Pyrimidine

[0064] Water (20 mmoles) is added to a solution of1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25ml). The reaction mixture is stirred for 6{fraction (1/2 )}h at 40° C.The resulting mixture is slowly added to a mixture consisting of4-fluorobenzamidine hydrochloride (10 mmoles),4-trifluoromethyl-2-methylpyrazol-1-on (11 mmoles), potassium carbonate(60 mmoles) and dimethoxyethane (50 ml), which is stirred under reflux.When the addition of 3,3-dichloroacrolein solution is completedadditional 4-fluorobenzamidine hydrochloride (0.5 mmoles) is added. Thereaction mixture is stirred for 2 hours under reflux and subsequentlycooled down to ambient temperature. filtered through a silica, and theorganic phase is concentrated in vacuo. The residue is purified bychromatography on SiO₂ (petrol ethers/ethylacetate: 2/1) to yield 1.40 g(46%) of beige crystals having a melting point of 101-102° C.

EXAMPLE 16 Preparation of4-(2-Difluoromethoxypyridin-4-Yloxy)-2-(Pyrazin-2-yl)-Pyrimidine

[0065] Water (20 mmoles) is added to a solution of1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25ml). The mixture is stirred for 2 h at 60° C. The resulting mixture isslowly added to a mixture consisting of a pyrazine-2-carboxamidinehydrochloride (10 mmoles). 2-difluoromethoxypyridin-4-ol (10 mmoles),potassium carbonate (60 mmoles) and dimethoxyethane (50 ml), which isstirred under reflux. When the addition of 3,3-dichloroacrolein solutionis completed additional pyrazine-2-carboxamidine hydrochloride (0.5mmoles) is added. The reaction mixture is stirred for 2 hours underreflux and subsequently cooled down to ambient temperature, filteredthrough silica, and the organic phase is concentrated in vacuo. Theresidue is purified by chromatograph on SiO₂ (ethyl acetate) to yield2,60 g (82%) of beige crystals having a melting point of 128-129° C.

EXAMPLE 17 Preparation of4-(3-Trifluoromethylphenoxy)-2-(3,5-Dimethylpyrazol1-yl-Pyrimidine

[0066] Water (20 mmoles) is added to a solution of1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25ml). The mixture is stirred for 2 h at 90° C. The resulting mixture isslowly added to a mixture consisting of a3,5-dimethylpyrazole-1-carboxamidine nitrate (10 mmoles),3-trifluoromethylphenol (10 mmoles), potassium carbonate (60 mmoles) anddimethoxyethane (50 ml), which is stirred under reflux. When theaddition of 3,3-dichloroacrolein solution is completed additional3,5-dimethylpyrazole-1-carboxamidine nitrate (0.5 mmoles) is added. Thereaction mixture is stirred for 10 hours under reflux and subsequentlycooled down to ambient temperature, filtered through silica, and theorganic phase is concentrated in vacuo. The residue is purified bychromatography on SiO₂ (ethyl acetate) to give 2,2 g of a yellow solid.The solid was washed with petrol ether (50 ml) to yield 1,75 g (52 %) ofcoloroless crystals having a melting point of 101-102° C.

What is claimed is:
 1. A process for the preparation of substitutedpyrimidines of formula I,

wherein R¹ and R² each independently represent an optionally substitutedalkyl, cycloalkyl, phenyl or heteroaryl group, R³ and R⁴ eachindependently represent a hydrogen atom or an optionally substitutedalkyl or phenyl group, and X represents O or S, which comprises reactingan amidine of formula II

or a salt thereof, wherein R¹ has the meaning given for formula I, witha 3,3-disubstituted vinylcarbonyl compound of formula III

wherein R³ and R⁴ have the meaning given, and L represent a halogen atomor a group of formula —X—R², (a) in an inert solvent, in the presence ofa base and a compound of formula IV H—X—R²  (IV) wherein X and R² havethe meaning given, in the event that L represent a halogen atom, or (b)in an inert solvent and in the presence of a base, in the event that Lrepresents a group of formula —X—R².
 2. A process according to claim 1which comprises that the reaction is carried out in the presence of abase selected from the group consisting of alkali hydrogencarbonates,alkali carbonates and tertiary amines.
 3. A process according to claim1, wherein the amidine of formula II to 3,3-disubstituted vinylcarbonylcompound of formula IlI molar ratio is from 1:5 to 1:05.
 4. A processaccording to claim 1, wherein the reaction step further comprisesstirring a mixture consisting essentially of the amidine of formula IIthe 3,3-disubstituted vinylcarbonyl compound of formula III, the inertdiluent, a base and an optionally substituted alcohol, thioalcohol,phenol or thiophenol at a temperature from 0° C. to 150° C.
 5. A processaccording to claim 4, wherein the inert diluent is selected from thegroup consisting of acetonitril, benzene, toluene, xylene, hexane,cyclohexane, dichloromethane, tetrachloromethane, diethylether,diisopropylether, tert-butylmethylether, 2,2-dimethoxypropane,dimethoxyethane, diethoxyethane, tetrahydrofuran, tetrahydropyran,dimethylformamide, dimethylacetamide, N-methylpyrrolidone,dimethylsulfoxide and dioxane, and a mixture thereof.
 6. A processaccording to claim 1, wherein R¹ represents a phenyl group which issubstituted by at least one halogen atom, or at least one alkyl, alkoxy,haloalkyl or haloalkoxy group.
 7. A process according to claim 6,wherein R¹ represents a 4-trifluoromethylphenyl group.
 8. A processaccording to claim 1 for the preparation of a 4-phenoxy-2-arylpyrimidineof formula I wherein R¹ and R² each independently represent a phenylgroup which is substituted by at least one halogen atom, and/or at leastone alkyl, alkoxy, haloalkyl or haloalkoxy group, and X represents O,which comprises that the reaction step is carried out in the presence ofa phenol, which is substituted by at least one halogen atom, and/or atleast one alkyl, alkoxy, haloalkyl or haloalkoxy group.
 9. A processaccording to claim 8, wherein the reaction step is carried out in thepresence of 3-trifluoromethylphenol.
 10. A process according to claim 1,wherein the 3,3-disubstituted vinylcarbonyl compound is3,3-dichloroacrolein.
 11. A process according to claim 10, wherein3,3-dichloroacrolein is prepared by an in-situ hydrolysis of a1,1,1,3-tetrachloro-3-alkoxypropane.
 12. The compound of formula 1A,

wherein R³ and R⁴ are as defined in claim 1, and R¹ represents anoptionally substituted C₃-8 cycloalkyl or pyrazin-2-yl group, R⁵represents a halogen atom or a haloalkyl or haloalkoxy group, and W—Vrepresents N—C,H, S—CH, N—CH—CH, CH—CH—CH or N—N(R⁶), in which R⁶represents a C₁₋₄ alkyl group.